Ajit Sood

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Ulcerative colitis and Crohns disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organization: When to Start, When to Stop, Which Drug to Choose, and How to Predict Response?

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohns disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

The Probiotic Preparation, VSL#3 Induces Remission in Patients With Mild-to-Moderately Active Ulcerative Colitis

BACKGROUND & AIMS Probiotics can maintain ulcerative colitis (UC) in remission effectively, but little is known of their ability to induce remission. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of a high-potency probiotic, VSL#3, for the treatment of mild-to-moderately active UC. METHODS Adult patients with mild-to-moderate UC were assigned randomly to groups that were given 3.6 x 10(12) CFU VSL#3 (n = 77) or placebo (n = 70), twice daily for 12 weeks. The primary end point was a 50% decrease in the Ulcerative Colitis Disease Activity Index (UCDAI) at 6 weeks. The secondary end points included remission by 12 weeks and reduction in total individual UCDAI parameters from baseline at 12 weeks. Intention-to-treat analysis was performed. RESULTS At week 6, the percentage of patients with an improvement in UCDAI score that was greater than 50% was significantly higher in the group given VSL#3 (25; 32.5%) than the group given placebo (7; 10%) (P = .001). At week 12, there were 33 patients given VSL#3 (42.9%) who achieved remission, compared with 11 patients given placebo (15.7%) (P < .001). Furthermore, significantly more patients given VSL#3 (40; 51.9%) achieved a decrease in their UCDAI that was greater than 3 points, compared with those given placebo (13; 18.6%) (P < .001). The VSL#3 group had significantly greater decreases in UCDAI scores and individual symptoms at weeks 6 and 12, compared with the placebo group. CONCLUSIONS VSL#3 is safe and effective in achieving clinical responses and remissions in patients with mild-to-moderately active UC.

World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohns disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

Incidence and prevalence of ulcerative colitis in Punjab, North India

Introduction: Ulcerative colitis occurs worldwide. It is considered common in most of Europe and North America and uncommon in most of the developing Asian countries. The incidence/prevalence of ulcerative colitis varies not only according to geographical region but also with race and ethnicity. There are no reported data from India on the incidence of the disease and its prevalence. Material and methods: A house to house survey was conducted by questionnaire, formulated to enquire about symptoms that are suggestive of ulcerative colitis. Those with prolonged diarrhoea with or without rectal bleeding were considered as suspected cases. These suspected cases were subjected to video sigmoidoscopy/colonoscopy and rectal biopsy. In addition, patients already diagnosed and receiving treatment for ulcerative colitis, encountered during the survey, were reviewed. Resurvey of the same areas was conducted after a one year interval to detect new cases. Using direct methods, standardised rates were calculated using world standard population weights 22, 18, 16, 12, 12, 9, 7, 3, and 1 for each 10 year age group. Standardised rates were also obtained separately for males, females, and combined populations, using the Punjab state 1991 population census data. Rates were also estimated according to UK 2000 population data. Ninety five per cent confidence intervals (95% CI) of prevalence and incidence rates of ulcerative colitis were estimated under the assumption that the distribution of cases followed a Poisson probability model. Results: A total population of 51 910 were screened from January to March 1999. We identified 147 suspected cases and of these 23 were finally established as ulcerative colitis cases, giving a crude prevalence rate of 44.3 per 100 000 inhabitants (95% CI 29.4–66.6). A second visit to the same areas after one year identified 10 suspected cases in a population of 49 834. Of these, three were confirmed as “definite” ulcerative colitis giving a crude incidence rate of 6.02 cases per 100 000 inhabitants (95% CI 1.2–17.6). Conclusions: This is the first population based study from India reporting on the incidence and prevalence of ulcerative colitis. The disease frequency is not much less than that reported from Europe and North America.

Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial).

OBJECTIVES:Cirrhotics with minimal hepatic encephalopathy (MHE) have a poor health-related quality of life (HRQOL). Treatment of MHE is still evolving. The aim of this double-blind randomized pilot study was to assess the efficacy of rifaximin in improving neuropsychometric (NP) test performance and HRQOL in patients with MHE.METHODS:MHE was diagnosed if any two NP tests (number and figure connection tests, picture completion, digit symbol, and block design tests) were deranged beyond 2 s.d. of normal. HRQOL was assessed using the sickness impact profile (SIP) questionnaire.RESULTS:A total of 486 patients with cirrhosis were screened and 284 were found eligible. Out of these 115 (40.9%) had MHE, of which 21 refused consent and 94 were randomized to receive placebo (n=45) and rifaximin (n=49; 1200 mg/day) for 8 weeks. At the end of treatment, significantly more number of patients in rifaximin group showed reversal of MHE (75.5% (37/49) vs. 20% (9/45) in placebo group; P < 0.0001). Rifaximin group also showed significant reduction in mean number of abnormal NP tests (baseline, 2.35 (95% confidence interval (CI), 2.17–2.53); 2 weeks, 1.29 (95% CI, 1.02–1.56), P=0.002; 8 weeks, 0.81 (95% CI, 0.61–1.02), P=0.000), compared with placebo group (baseline, 2.31 (95% CI, 2.03–2.59); 2 weeks, 2.03 (95% CI, 1.74–2.31); 8 weeks, 1.97 (95% CI, 1.69–2.25), P>0.05). The mean total SIP score also improved significantly in rifaximin group (baseline, 11.67 (95% CI, 10.31–13.03); 8 weeks, 6.45 (95% CI, 5.59–7.30); P=0.000) compared with placebo group (baseline, 9.86 (95% CI, 8.66–11.06); 8 weeks, 8.51 (95% CI, 7.35–9.67); P=0.82). Improvement in HRQOL correlated with improvement in NP tests. Rifaximin was well tolerated.CONCLUSIONS:Rifaximin significantly improves both cognitive functions and HRQOL in patients with MHE.

Prevalence of celiac disease among school children in Punjab, North India

Background:  Celiac disease, as of today, is said to exist in almost all parts of the world, although it is rare among people of purely African–Caribbean, Japanese and Chinese background. The disease has also been considered uncommon in India until recently. Hospital records have revealed an increasing trend of the disease in predominantly wheat‐eating areas of North India. The aim of the present study was to determine the prevalence of celiac disease among school children in Punjab, North India.

The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis

Background. The search is on to find more effective drug regimens for patients with severe ulcerative colitis, as conventional drugs such as sulfasalazine and its congeners fail to prevent relapse in a significant number of patients. Azathioprine has also been reported to be useful as a steroid-sparing drug in patients who suffer from frequent relapses. As these drugs when used individually fail to sustain remission in a significant number of patients, we evaluated the combination of these two drugs. Methods. Thirty-five newly diagnosed patients with severe ulcerative colitis were randomized into two groups; group A (combination therapy) received sulfasalazine and azathioprine, while group B (sulfasalazine monotherapy) received sulfasalazine and placebo. In addition, all the patients received steroids initially to achieve clinical remission. The patients were followed-up for a period of 1 year. The therapeutic outcome was measured by the number of patients who suffered relapse in each group. Results. All the patients completed the 1-year study period. While 4 patients (23.5%) in group A suffered relapse of disease, 10 (55.6%) in group B suffered relapse, the difference being statistically significant. The relapse-free period was also significantly longer in group A. Conclusions. Combination therapy (sulfasalazine and azathioprine) is more effective than sulfasalazine and placebo in the maintenance of remission in patients with severe ulcerative colitis.

Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis B.

BACKGROUND:Lower hepatitis B virus DNA (HBV DNA) levels are associated with better responses in chronic hepatitis B (CHB). It is unclear whether an initial phase of antiviral treatment to lower HBV DNA levels before adding immunomodulator therapy is more effective than the strategy of using immunomodulators from the beginning.AIM:The aim of the study was to compare the efficacy of lamivudine followed by pegylated-interferon (peg-IFN) therapy with placebo followed by peg-IFN therapy in HBeAg-positive CHB patients.PATIENTS AND METHODS:Sixty-three treatment-naive HBeAg-positive patients with histologically proven CHB and alanine aminotransferase (ALT) > 1.2 × upper limit of normal (ULN) received placebo for 4 wk followed by peg-IFN 1.0 μg/kg/wk for next 24 wk (group A, N = 27; age 32 ± 11yr; M:F = 25:2) or lamivudine 100 mg per day for 4 wk followed by peg-IFN 1.0 μg/kg/wk for next 24 wk (group B, N = 36; age 32.5 ± 10.5 yr; M:F = 31:5). Patients were followed for next 24 wk after completion of treatment. Biochemical and virologic responses were assessed at weeks 4, 28, and 52 and analysis was done on intention-to-treat basis.RESULTS:At wk 4, mean ± SD of log change in DNA from baseline was 0.2594 ± 1.7873 in group A and 1.2186 ± 1.6347 in group B, respectively (P = 0.032). At week 28, undetectable HBV DNA was seen in eight (29.6%) and 16 (44.4%) patients in groups A and B, respectively (P = 0.298). At week 28, HBeAg loss occurred in eight (29.6%) in group A and 15 (41.7%) in group B (P = 0.43). Six months posttherapy, at week 52, undetectable HBV DNA was seen in four (14.8%) and 18 (50%) in groups A and B, respectively (P = 0.028) and HBeAg loss was maintained in four (14.8%) and 14 (38.9%) (P = 0.05) patients. Normal ALT was seen in five (18.5%) and 10 (27.8%) at week 28 (P = 0.552) and five (18.5%) and 13 (36.1%) at week 52 (P = 0.159) in groups A and B, respectively. There was a significant correlation among achievement of HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28 (P = 0.008) and 52 (P < 0.001) and HBV DNA levels at week 4.CONCLUSIONS:The strategy of using an antiviral initially to decrease HBV DNA levels before adding an immunomodulatory agent leads to improved sustained virological response as compared with using immunomodulator from the start.